The molecular mechanisms determining magnitude and duration of inflammatory
pain are still unclear. We assessed the contribution of
G protein-coupled receptor kinase (GRK)-6 to inflammatory
hyperalgesia in mice. We showed that GRK6 is a critical regulator of severity and duration of
cytokine-induced
hyperalgesia. In GRK6⁻/⁻ mice, a significantly lower dose (100 times lower) of intraplantar
interleukin (IL)-1β was sufficient to induce
hyperalgesia compared with wild-type (WT) mice. In addition, IL-1β
hyperalgesia lasted much longer in GRK6⁻/⁻ mice than in WT mice (8 d in GRK6⁻/⁻ versus 6 h in WT mice).
Tumor necrosis factor (TNF)-α-induced
hyperalgesia was also enhanced and prolonged in GRK6⁻/⁻ mice. In vitro, IL-1β-induced p38 phosphorylation in GRK6⁻/⁻ dorsal root ganglion (DRG) neurons was increased compared with WT neurons. In contrast, IL-1β only induced activation of the
phosphatidylinositol (
PI) 3-kinase/Akt pathway in WT neurons, but not in GRK6⁻/⁻ neurons. In vivo, p38 inhibition attenuated IL-1β- and TNF-α-induced
hyperalgesia in both genotypes. Notably, however, whereas
PI 3-kinase inhibition enhanced and prolonged
hyperalgesia in WT mice, it did not have any effect in GRK6-deficient mice. The capacity of GRK6 to regulate
pain responses was also apparent in
carrageenan-induced
hyperalgesia, since thermal and mechanical
hypersensitivity was significantly prolonged in GRK6⁻/⁻ mice. Finally, GRK6 expression was reduced in DRGs of mice with chronic neuropathic or inflammatory
pain. Collectively, these findings underline the potential role of GRK6 in pathological
pain. We propose the novel concept that GRK6 acts as a
kinase that constrains neuronal responsiveness to IL-1β and TNF-α and
cytokine-induced
hyperalgesia via biased
cytokine-induced p38 and
PI 3-kinase/Akt activation.